Is MECP2 p.Pro399Thr (c.1195C>A) pathogenic?

MECP2 p.Pro399Thr (c.1195C>A) is classified Conflicting classifications of pathogenicity in MECP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-11). AlphaMissense: likely benign (0.0831); Very rare (popmax 0.00221%, amr); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro399Thr (c.1195C>A)?

MECP2 p.Pro399Thr (c.1195C>A) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro399Thr (c.1195C>A) in the general population?

MECP2 p.Pro399Thr (c.1195C>A) is very rare (popmax 0.00221%, amr) (gnomAD).

How is MECP2-related severe neonatal encephalopathy inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MECP2 p.Pro399Thr (c.1195C>A)?

AlphaMissense predicts likely benign (score 0.0831) — an in-silico prediction, not a clinical call.

MECP2 p.Pro399Thr

c.1195C>A · rs1171658384 · VCV1206568

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.0831	likely benign
REVEL	0.43	indeterminate
SaProt	LLR -13.59	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 1.6, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	17.66	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P387T vs ClinVar P399T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% Admixed American · 1/45,231 alleles

Filtering AF 0.000166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000589% 7/1,189,406 alleles · very rare exomes 6/1,081,758 · genomes 1/107,648 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00221%	45,231
South Asian	0.00178%	56,238
European (non-Finnish)	0.000566%	176,681

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MECP2
Protein: p.Pro399Thr
Coding: c.1195C>A
MANE Select: NM_001110792
dbSNP: rs1171658384
Type: single nucleotide variant
Location: chrX:154030669 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 387 UniProt numbering: a UniProt-annotated variant site (in rtt); the 'disordered' region

Full MECP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

severe neonatal-onset encephalopathy with microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Pro399Leu Benign ★★★ ⚠ same residue
MECP2 p.Pro399Ser Uncertain significance ★★ ⚠ same residue
MECP2 p.Pro399= Likely benign ★ same residue
MECP2 p.Pro399_Pro400insTer Pathogenic/Likely pathogenic ★★ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A Pathogenic ★★★ same condition
MECP2 p.Ala291Val Likely pathogenic ★★★ ⚠ same condition
MECP2 p.Arg127His Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mecp2-p-pro399thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown